ABSTRACT HIV and Alzheimer?s disease (AD) brains share amyloid pathology as a contributing factor to cognitive decline that develops in the course of these diseases. In addition, both HIV infection and AD are associated with increased generation and release of extracellular vesicles (ECVs) that contain amyloid beta (A?) and are involved its intercellular transfer. Finally, the pool of neural progenitor cells (NPCs) is affected in both HIV infection and AD, leading to alterations of the learning and memory processes in HIV and AD patients. Thus, studies on shared mechanisms between HIV-infected brains and AD, with focus on A? and ECVs, may provide common pathways to treatment of these diseases. Our results, generated in the course of the parent grant, indicate that exposure to ECVs carrying A? (A?-ECVs) negatively affects differentiation of NPCs to mature neurons; however, the mechanisms of these effects are unknown. In the present supplement, we hypothesize that an underlying cause of altered neurogenesis may be mitochondrial dysfunction, which is a prominent feature of both HIV infection and AD. Therefore, we propose to extend our original proposal on studies on the impact of A?- ECVs on mitochondrial functions of NPCs. The central hypothesis of this supplement is that exposure to A?-ECVs induces mitochondrial dysfunction of NPCs, leading to the induction of inflammatory responses, and resulting in aberrant neurogenesis. Consistent with the parent grant, the outcome of the proposed studies will be focused on differentiation of NPCs to mature neurons. When successfully completed, this supplement may lead to the development of future therapeutic interventions influencing ECV formation and interactions with NPCs that can attenuate the dynamic and severity of cognitive decline both in HIV infection and AD.